In designing an effective radiopharmaceutical tracer for use as a diagnostic agent, it is imperative that the drugs have appropriate in vivo targeting and pharmacokinetic properties. Fritzberg et al. (1992, J. Nucl. Med., 33:394) state further that radionuclide chemistry and associated linkages underscore the need to optimize the attachment and labeling chemical modifications of the biomolecule carrier. Hence the type of radionuclide, the type of biomolecule and the method used for linking them to one another may have a crucial effect onto the radiotracer properties.
Peptides are biomolecules that play a crucial role in many physiological processes including actions as neurotransmitters, hormones, and antibiotics. Research has shown their importance in such fields as neuroscience, immunology, pharmacology, and cell biology. Some peptides can act as chemical messenger. They bind to receptor on the target cell surface and the biological effect of the ligand is transmitted to the target tissue. Hence, the specific receptor binding property of the ligand can be exploited by labeling the ligand with a radionuclide. Theoretically, the high affinity of the ligand for the receptor facilitates retention of the radio labeled ligand in receptor expressing tissues. However, it is still under investigation which peptides can be efficiently labeled and under which conditions the labeling shall occur. It is well known that receptor specificity of ligand peptide may be altered during chemical reaction. Therefore an optimal peptidic construct has to be determined.
Tumors overexpress various receptor types to which peptides bind specifically. The following publications of Boerman et al., Seminar in Nuclear Medicine, 2000, 30(3), 195); Reubi et al. J. Nucl. Med., 2005, 46, (supp1) 67S; Reubi, J. C., Endocrine Reviews, 2003, 24(4), 389 provide a non exhaustive list of peptides that specifically bind to cell surface receptors in neoplasms, i.e., somatostatin, vasoactive intestinal peptide (VIP), Bombesin binding to Gastrin-releasing peptide (GRP) receptor, Gastrin, Cholecystokinin (CCK), and Calcitonin.
The potential utility of metal labeled receptor specific peptides for scintigraphic imaging and radiotherapy is exemplified by somatostatin analogs, e.g., 111In-DTPA conjugated Octreotide, an FDA approved diagnostic imaging agent, Octreoscan®, marketed by Covidien in the United States (Lowbertz et al., Seminars in Oncology, 1994, 1) and Reubi et al., J. Nucl. Med., 2005, 46, 67S-75S and references therein, respectively. Octreotide and its analogs have been covalently linked to several imaging metal isotopes (99mTc, 111In 68Ga) and to therapeutic metal isotopes (102Rh, 186/188Re, 153Sm, 90Y, 166Ho, 177Lu). The metal labeled conjugates specifically bind to the receptor, and upon binding to the receptor, the construct is internalized by the receptor and the metal labeled receptor specific peptides or their metabolites are trapped in the targeted cells.
The foregoing principle is further extended to GRP receptor avid peptides (peptides have high affinity for the receptor) in which metal conjugated Bombesin agonists are used for scintigraphic imaging and radiotherapy. (Smith et al., Anticancer Res, 23 (2003), 63-70; Baidoo et al., Bioconjug. Chem., 9 (1998), 218-225; Gali et al., Bioconjug. Chem., 12 (2001), 354-363; Smith et al., Bioconjug. Chem., 14 (2003), 93-102, Cancer Res., 63 (2003), 4082-4088; Rogers et al., In, M. Nicolini and U. Mazzi, Editors, Technetium, rhenium and other metals in chemistry and nuclear medicine, SGE Editoriali, Italy (1999), 519-525; Zhang et al., Cancer Res., 64 (2004), 6707-6715; Lantry et al., EANM, Helsinki (Finland) (2004); Linder et al., J. Nucl. Med., 45, (2004) (5), 169P [abstract 482]. Chen et al., J Nucl. Med., 45 (2004), 1390-1397; Johnson et al., Cancer Biother Radiopharm. 2006, 21(2), 155-66, Smith et al., Nucl. Med. Biol., 2005, 32 733-40).
In Chen et al. (Appl. Radiat. Isot., 2007, (In Press)), Waser et al. (Eur. J. Nucl. Med. Mol. Imaging. 2007 34, 95-100) and Lantry et al. (J. Nucl. Med., 2006, 47, 1144-52) imaging and radiotherapy of a bombesin agonist, 177Lu-DOTA coupled to —NH—CH2—CO-[4-aminobenzoyl]-QWAVGHLM-NH2)) (177Lu-AMBA), has been described.
Several patents and patent applications refer to metal labeled Bombesin agonists. Volkert et al. (US 2007/0065362 A) claim metal labeled Bombesin agonists of the general structure Metal labeling moiety-Spacer group-Bombesin agonist for imaging and therapeutic use. Other patents and patent applications by the same inventors include: U.S. Pat. No. 6,921,526 B (2005), U.S. Pat. No. 7,060,247 B, U.S. Pat. No. 7,147,838 B (2006) and WO 2002/087631 A1.